Abstract:

The present invention relates to compounds and methods which may be useful
as inhibitors of phosphodiesterase 4 (PD E4) for the treatment or
prevention of inflammatory diseases and other diseases involving elevated
levels of cytokines and proinflammatory mediators.

Claims:

1. A compound of structural Formula II ##STR00041## or a salt, ester, or
prodrug thereof, wherein:X1 is selected from the group consisting of
O, N(R14) and (CR15R16);X2 is selected from the group
consisting of (CR18R19), COR18, and null;X is selected
from the group consisting of N(R17) and (CR20R21);R1
and R2 are independently selected from the group consisting of
--(CH2)sG1G2G3, acyl, acylalkyl, carboxyalkyl,
cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl, amino, alkyl, alkylalkoxy,
aminoalkyl, alkenyl, alkynyl, carboxyl, carboxyalkyl, ether, heteroalkyl,
haloalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,
heterocycloalkylalkyl, aralkyl, aryl, guanidine, heteroaryl,
heteroaralkyl, hydrogen and hydroxyalkyl, any of which may be optionally
substituted;s is 1-8;G1 is selected from the group consisting of
alkoxy, amino, amido, carbonyl, hydroxy, ether, an amino acid, and
null;G2 is selected from the group consisting of alkyl, alkoxy, amino,
aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl, carboxylalkylamino,
guanidine, an amino acid, and null, any of which may be optionally
substituted;G3 is selected from the group consisting of alkyl,
alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid,
phosphonate, phosphoamide, and null, any of which may be optionally
substituted;R3 and R4 are each independently selected from the
group consisting of hydrogen, halogen, alkoxy and lower alkyl;R5 is
selected from the group consisting of
--(CR8R9)mW(CR10R11)n-- and
--(CR12R13)p--;W is selected from the group consisting of
O, N(R7), C(O)N(R7), and SOq;m, n, and q are independently
0, 1 or 2;p is 1 or 2;R6 is selected from the group consisting of
carboxyl, alkylcarboxy, amido, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, alkyl, heteroalkyl, acyl, and hydroxamic acid, any of
which may be optionally substituted;R7, R8, R9, R10,
R11, R12, and R13 are independently selected from the
group consisting of hydrogen and optionally substituted lower
alkyl;R14 and R17 are independently selected from the group
consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl,
haloalkyl, aminoalkyl, and a bond;R15, R16, R19, R20,
and R21 are independently selected from the group consisting of
hydrogen, halogen, lower alkyl, haloalkyl, hydroxyalkyl,
heterocycloalkylalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy
and a bond; andR18 is selected from the group consisting of halogen,
lower alkyl, haloalkyl, hydroxyalkyl, heterocycloalkylalkyl, alkoxy,
haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond.

2. The compound as recited in claim 1, having any one of structural
Formulas III, IV, V, or VI ##STR00042## or a salt, ester, or prodrug
thereof, wherein:R1 and R2 are independently selected from the
group consisting of --(CH2)sG1G2G3, acyl,
acylalkyl, carboxyalkyl, cyanoalkyl, alkoxy, alkoxyalkyl, amidoalkyl,
amino, alkyl, alkylalkoxy, aminoalkyl, alkenyl, alkynyl, carboxyl,
carboxyalkyl, ether, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl,
heterocycloalkyl, heterocycloalkylalkyl, aralkyl, aryl, guanidine,
heteroaryl, heteroaralkyl, hydrogen and hydroxyalkyl, any of which may be
optionally substituted;s is 1-8;G1 is selected from the group
consisting of alkoxy, amino, amido, carbonyl, hydroxy, ether, an amino
acid, and null;G2 is selected from the group consisting of alkyl,
alkoxy, amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl,
carboxylalkylamino, guanidine, an amino acid, and null, any of which may
be optionally substituted;G3 is selected from the group consisting
of alkyl, alkoxy, amino, hydroxy, ether, carboxyl, hydroxamic acid, an
amino acid, phosphonate, phosphoamide, and null, any of which may be
optionally substituted;R3 and R4 are independently selected
from the group consisting of hydrogen, halogen, alkoxy and lower
alkyl;R5 is selected from the group consisting of
--(CR8R9)mW(CR10R11)n-- and
--(CR2R3)p--;W is selected from the group consisting of O,
N(R7), C(O)N(R7), and SOq;m, n, and q are independently 0,
1 or 2;p is 1 or 2;R6 is selected from the group consisting of
carboxyl, alkylcarboxy, amido, aryl, heteroaryl, cycloalkyl,
heterocycloalkyl, alkyl, heteroalkyl, acyl, and hydroxamic acid, any of
which may be optionally substituted;R7, R8, R9, R10,
R11, R12, and R13 are independently selected from the
group consisting of hydrogen and optionally substituted lower
alkyl;R15 and R20 are each independently selected from the
group consisting of hydrogen, halogen, lower alkyl, hydroxyalkyl,
heterocycloalkylalkyl, haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl,
and aminoalkoxy; andR18 is selected from the group consisting of
halogen, lower alkyl, hydroxyalkyl, heterocycloalkylalkyl, haloalkyl,
alkoxy, haloalkoxy, amino, aminoalkyl, and aminoalkoxy.

3. The compound as recited in claim 2, wherein R3 and R4 are
both hydrogen.

4. The compound as recited in claim 3, wherein R6 is selected from
the group consisting of phenyl, pyridine, pyrimidine, pyridazine, and
pyrazine, any of which may be optionally substituted.

5. The compound as recited in claim 4, wherein:R5 is
--(CR8R9)mW(CR10R11)n--;m and n are both
0;W is N(R7); andR7 is hydrogen.

6. The compound as recited in claim 5, wherein R2 is lower alkyl.

7. The compound as recited in claim 6, wherein:R1 is selected from
the group consisting of --(CH2)sG1G2G3, lower
alkyl, cycloalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which
may be optionally substituted;s is 1-6;G1 is selected from the group
consisting of amino, amido, and null;G2 is selected from the group
consisting of alkoxy, aryl, halo, heterocycloalkyl, and null, any of
which may be optionally substituted; andG3 is selected from the
group consisting of alkyl, carboxyl, and null, any of which may be
optionally substituted.

8. The compound as recited in claim 7, wherein R2 is methyl.

9. The compound as recited in claim 8, wherein R6 has a formula
selected from the group consisting of: ##STR00043## R22, R23,
R24, R25 and R26 are independently selected from the group
consisting of hydrogen, halogen, hydroxyl, lower alkyl, lower alkoxy,
lower haloalkyl, lower haloalkoxy, amino, and carboxyl.

10. A compound selected from the group consisting of Examples 1 to 30.

11. A compound as recited in claim 1 for use as a medicament.

12. A compound as recited in claim 1 for use in the manufacture of a
medicament for the prevention or treatment of a disease or condition
ameliorated by the inhibition of PDE4.

13. A pharmaceutical composition comprising a compound as recited in claim
1 together with a pharmaceutically acceptable carrier.

14. A method of inhibition of PDE4 comprising contacting PDE4 with a
compound as recited in claim 1.

15. A method of treatment of a PDE4-mediated disease comprising the
administration of a therapeutically effective amount of compound as
recited in claim 1 to a patient in need thereof.

16. The method as recited in claim 15 wherein said PDE4-mediated disease
is an ophthalmic disease.

18. The method as recited in claim 13, wherein said PDE4 is the PDE4B
subtype.

19. A method of treatment of a PDE4-mediated disease comprising the
administration of:a. a therapeutically effective amount of said compound
as recited in claim 1; andb. another therapeutic agent.

Description:

[0001]This application claims the benefit of U.S. Provisional Applications
No. 60/819,509, filed Jul. 7, 2006, and No. 60/886,825, filed Jan. 26,
2007, the disclosures of which are hereby incorporated by reference as if
written herein in their entireties.

[0002]Disclosed herein are potent and selective new bicyclic heteroaryl
compounds, certain of which have been found to be useful as inhibitors of
phosphodiesterase 4 (PDE4), compositions comprising the same, and their
application as pharmaceuticals for the treatment of disease. Methods of
inhibition of PDE4 activity are also provided, as well as methods for the
treatment of inflammatory diseases and other diseases involving elevated
levels of cytokines and proinflammatory mediators.

[0003]Chronic inflammation is a multi-factorial disease complication
characterized by activation of multiple types of inflammatory cells, for
example cells of lymphoid lineage (including T lymphocytes) and myeloid
lineage (including granulocytes, macrophages, and monocytes).
Proinflammatory mediators, including cytokines, such as tumor necrosis
factor (TNF) and interleukin-1 (IL-1), are produced by these activated
cells. Accordingly, an agent that suppresses the activation of these
cells, or their production of proinflammatory cytokines, would be useful
in the therapeutic treatment of inflammatory diseases and other diseases
involving elevated levels of cytokines.

[0004]Cyclic adenosine monophosphate (cAMP) is a second messenger that
mediates the biologic responses of cells to a wide range of extracellular
stimuli. When the appropriate agonist binds to specific cell surface
receptors, adenylate cyclase is activated to convert adenosine
triphosphate (ATP) to cAMP. It is theorized that the agonist induced
actions of cAMP within the cell are mediated predominately by the action
of cAMP-dependent protein kinases. The intracellular actions of cAMP are
terminated by either a transport of the nucleotide to the outside of the
cell, or by enzymatic cleavage by cyclic nucleotide phosphodiesterases
(PDEs), which hydrolyze the 3'-phosphodiester bond to form 5'-adenosine
monophosphate (5'-AMP). 5'-AMP is an inactive metabolite.

[0005]The superfamily of PDEs is subdivided into two major classes, class
I and class II, which have no recognizable sequence similarity. Class I
includes all known mammalian PDEs and is comprised of 11 identified
families that are products of separate genes. Some PDEs are highly
specific for hydrolysis of cAMP (PDE4, PDE7, PDE8), some are highly
cGMP-specific (PDE5, PDE6, PDE9), and some have mixed specificity (PDE1,
PDE2, PDE3, PDE10, PDE11). All of the characterized mammalian PDEs are
dimeric, but the importance of the dimeric structure for function in each
of the PDEs is unknown.

[0007]Elevated levels of cAMP in human myeloid and lymphoid lineage cells
are associated with the suppression of cell activation. The intracellular
enzyme family of PDEs, therefore, regulates the level of cAMP in cells.
PDE4 is a predominant PDE isotype in these cells, and is a major
contributor to cAMP degradation. Accordingly, the inhibition of PDE
function would prevent the conversion of cAMP to the inactive metabolite
5'-AMP and, consequently, maintain higher cAMP levels, and, accordingly,
suppress cell activation.

[0011]Additionally, several properties of TNFα, such as stimulation
of collagenases, stimulation of angiogenesis in vivo, stimulation of bone
resorption, and an ability to increase the adherence of tumor cells to
endothelium, are consistent with a role for TNF in the development and
metastatic spread of cancer in the host. TNFα recently has been
directly implicated in the promotion of growth and metastasis of tumor
cells (see Orosz et al., J. Exp. Med., 177, pp. 1391-1398, (1993)).

[0012]Investigators have shown considerable interest in the use of PDE4
inhibitors as anti-inflammatory agents. Early evidence indicates that
PDE4 inhibition has beneficial effects on a variety of inflammatory cells
such as monocytes, macrophages, T-cells of the Th-1 lineage, and
granulocytes. The synthesis and/or release of many proinflammatory
mediators, such as cytokines, lipid mediators, superoxide, and biogenic
amines, such as histamine, have been attenuated in these cells by the
action of PDE4 inhibitors. The PDE4 inhibitors also affect other cellular
functions including T-cell proliferation, granulocyte transmigration in
response to chemotoxic substances, and integrity of endothelial cell
junctions within the vasculature.

[0013]The design, synthesis, and screening of various PDE4 inhibitors have
been reported. Methylxanthines, such as caffeine and theophylline, were
the first PDE inhibitors discovered, but these compounds are nonselective
with respect to which PDE is inhibited. The drug rolipram, an
antidepressant agent, was one of the first reported specific PDE4
inhibitors, with a reported IC50 of about 200 nM with respect to
inhibiting recombinant human PDE4.

[0014]Investigators have continued to search for PDE4 inhibitors that are
more selective with respect to inhibiting PDE4, that have a lower
IC50 than rolipram, and that avoid the undesirable central nervous
system (CNS) side effects, such as retching, vomiting, and sedation,
associated with the administration of rolipram. In addition, several
companies are now undertaking clinical trials of other PDE4 inhibitors.
However, problems relating to efficacy and adverse side effects, such as
emesis and central nervous system disturbances, remain unsolved.

[0015]Accordingly, compounds that selectively inhibit PDE4, and that
reduce or eliminate the adverse side effects associated with prior PDE4
inhibitors, would be useful in the treatment of allergic and inflammatory
diseases, and other diseases associated with excessive or unregulated
production of cytokines, such as TNF. In addition, selective PDE4
inhibitors would be useful in the treatment of diseases that are
associated with elevated cAMP levels or PDE4 function in a particular
target tissue.

[0016]Novel compounds and pharmaceutical compositions useful as
anti-inflammatory agents via the inhibition of PDE4 have been found,
together with methods of synthesizing and using the compounds including
methods for inhibiting PDE4 in a patient by administering the compounds.

[0017]Disclosed herein is a class of compounds, certain of which have been
found to be useful in treating PDE4-mediated disorders and conditions,
defined by structural Formula I:

##STR00001##

[0018]wherein:

[0019]A is an optionally substituted saturated or unsaturated hydrocarbon
chain or a heteroatom-comprising hydrocarbon chain having from 3 to 5
atoms, forming a five- to seven-membered ring;

[0020]U, V, and W are independently selected from the group consisting of
O, N(R7b) and SOq;

[0023]G1 is selected from the group consisting of alkoxy, amino,
amido, carbonyl, hydroxy, ether, an amino acid, and null;

[0024]G2 is selected from the group consisting of alkyl, alkoxy,
amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl,
carboxylalkylamino, guanidine, an amino acid, and null, any of which may
be optionally substituted;

[0025]G3 is selected from the group consisting of alkyl, alkoxy,
amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid,
phosphonate, phosphoamide, and null, any of which may be optionally
substituted;

[0026]R3 and R4 are each independently selected from the group
consisting of hydrogen, halogen, alkoxy and lower alkyl;

[0027]R5 is selected from the group consisting of
--(CR8R9)mW(CR10R11)n-- and
--(CR12R13)p--;

[0028]m, n, and q are each independently 0, 1 or 2;

[0029]p is 1 or 2;

[0030]W is selected from the group consisting of O, N(R7),
C(O)N(R7), and SOq;

[0031]R6 is selected from the group consisting of carboxyl,
alkylcarboxy, amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
alkyl, heteroalkyl, acyl, and hydroxamic acid, any of which may be
optionally substituted;

[0032]R7, R7b, R8, R9, R10, R11, R12,
and R13 are each independently selected from the group consisting of
hydrogen and optionally substituted lower alkyl.

[0033]Certain compounds according to the present invention possess useful
PDE4 inhibiting or modulating activity, and may be used in the treatment
or prophylaxis of a disease or condition in which PDE4 plays an active
role. Thus, in broad aspect, the certain embodiments of the present
invention also provide pharmaceutical compositions comprising one or more
compounds disclosed herein together with a pharmaceutically acceptable
carrier, as well as methods of making and using the compounds and
compositions. Certain embodiments of the present invention provide
methods for inhibiting PDE4. Other embodiments of the present invention
provide methods for treating a PDE4-mediated disorder in a patient in
need of such treatment, comprising administering to said patient a
therapeutically effective amount of a compound or composition according
to the present invention. Related embodiments disclose the use of certain
compounds disclosed herein as therapeutic agents, for example, in
treating inflammatory diseases and other diseases involving elevated
levels of cytokines and proinflammatory mediators. The present invention
also contemplates the use of certain compounds disclosed herein for use
in the manufacture of a medicament for the treatment of a disease or
condition ameliorated by the inhibition of PDE4.

[0034]In further embodiments, compounds of the present invention have
structural formula II

##STR00002##

[0035]wherein:

[0036]X1 is selected from the group consisting of O, N(R14), and
(CR15R16);

[0037]X2 is selected from the group consisting of C(O),
(CR18R19)COR18, and null;

[0038]X3 is selected from the group consisting of C(O), N(R17)
and (CR20R21);

[0041]G1 is selected from the group consisting of alkoxy, amino,
amido, carbonyl, hydroxy, ether, an amino acid, and null;

[0042]G2 is selected from the group consisting of alkyl, alkoxy,
amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl,
carboxylalkylamino, guanidine, an amino acid, and null, any of which may
be optionally substituted;

[0043]G3 is selected from the group consisting of alkyl, alkoxy,
amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid,
phosphonate, phosphoamide, and null, any of which may be optionally
substituted;

[0044]R3 and R4 are independently selected from the group
consisting of hydrogen, halogen, alkoxy and lower alkyl;

[0045]R5 is selected from the group consisting of
--(CR8R9)mW(CR10R11)n-- and
--(CR12R13)p--;

[0046]m, n, and q are each independently 0, 1 or 2;

[0047]p is 1 or 2;

[0048]W is selected from the group consisting of O, N(R7),
C(O)N(R7), and SOq;

[0049]R6 is selected from the group consisting of carboxyl,
alkylcarboxy, amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
alkyl, heteroalkyl, acyl, and hydroxamic acid, any of which may be
optionally substituted;

[0050]R7, R8, R9, R10, R11, R12, and
R13 are independently selected from the group consisting of hydrogen
and optionally substituted lower alkyl;

[0051]R14 and R17 are independently selected from the group
consisting of hydrogen, halogen, hydroxyl, lower alkyl, hydroxyalkyl,
haloalkyl, alkoxy, haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond;

[0052]R15, R16, R19, R20, and R21 are
independently selected from the group consisting of hydrogen, halogen,
lower alkyl, haloalkyl, hydroxyalkyl, heterocycloalkylalkyl, alkoxy,
haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond; and

[0053]R18 is selected from the group consisting of hydrogen, halogen,
lower alkyl, haloalkyl, hydroxyalkyl, heterocycloalkylalkyl, alkoxy,
haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond.

[0062]G1 is selected from the group consisting of alkoxy, amino,
amido, carbonyl, hydroxy, ether, an amino acid, and null;

[0063]G2 is selected from the group consisting of alkyl, alkoxy,
amino, aryl, halo, haloalkyl, heterocycloalkyl, heteroaryl,
carboxylalkylamino, guanidine, an amino acid, and null, any of which may
be optionally substituted;

[0064]G3 is selected from the group consisting of alkyl, alkoxy,
amino, hydroxy, ether, carboxyl, hydroxamic acid, an amino acid,
phosphonate, phosphoamide, and null, any of which may be optionally
substituted;

[0065]R3 and R4 are independently selected from the group
consisting of hydrogen, halogen, alkoxy and lower alkyl;

[0066]R5 is selected from the group consisting of
--(CR8R9)mW(CR10R11)n-- and
--(CR12R13)p--;

[0067]m, n, and q are each independently 0, 1 or 2;

[0068]p is 1 or 2;

[0069]W is selected from the group consisting of O, N(R7),
C(O)N(R7), and SOq;

[0070]R6 is selected from the group consisting of carboxyl,
alkylcarboxy, amido, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,
alkyl, heteroalkyl, acyl, and hydroxamic acid, any of which may be
optionally substituted;

[0071]R7, R8, R9, R10, R11, R12, and
R13 are independently selected from the group consisting of hydrogen
and optionally substituted lower alkyl;

[0072]R15 and R20 are each independently selected from the group
consisting of hydrogen, halogen, lower alkyl, haloalkyl, alkoxy,
haloalkoxy, amino, aminoalkyl, and aminoalkoxy; and

[0073]R18 is selected from the group consisting of hydrogen, halogen,
lower alkyl, haloalkyl, hydroxyalkyl, heterocycloalkylalkyl, alkoxy,
haloalkoxy, amino, aminoalkyl, aminoalkoxy and a bond.

[0074]In further embodiments are provided compounds wherein R3 and
R4 are both hydrogen.

[0075]In yet further embodiments are provided compounds wherein R6 is
selected from the group consisting of phenyl, pyridine, pyrimidine,
pyridazine, and pyrazine, any of which may be optionally substituted.

[0076]In yet further embodiments are provided compounds wherein R6 is
selected from the group consisting of phenyl, pyridine, and pyrimidine,
any of which may be optionally substituted.

[0077]In yet further embodiments are provided compounds wherein:

[0078]R5 is --(CR8R9)mW(CR10R11)n--;

[0079]m and n are both 0;

[0080]W is N(R7); and

[0081]R7 is hydrogen.

[0082]In yet further embodiments are provided compounds wherein R6
has the formula

[0092]In yet further embodiments are provided compounds wherein R2 is
lower alkyl. In yet further embodiments, R2 is methyl.

[0093]In yet further embodiments are provided compounds wherein:

[0094]R1 is selected from the group consisting of
--(CH2)sG1G2G3, lower alkyl, cycloalkyl,
cycloalkylalkyl, and heterocycloalkyl, any of which may be optionally
substituted;

[0095]s is 1-6;

[0096]G1 is selected from the group consisting of amino, amido, and
null;

[0097]G2 is selected from the group consisting of alkoxy, aryl, halo,
heterocycloalkyl, and null, any of which may be optionally substituted;
and

[0098]G3 is selected from the group consisting of alkyl, carboxyl,
and null, any of which may be optionally substituted.

[0099]Compounds of the present invention may be selective amongst the PDE4
isoforms PDE4A, PDE4B, PDE4C, and PDE4D in various ways. For example,
compounds described herein may be selective for PDE4B and PDE4D over the
other two isoforms, be a pan-inhibitor of all the isoforms, or be
selective for only one isoform. In certain embodiments, compounds of the
present invention may be selective for PDE4B over other isoforms.

[0100]The present invention also relates to a method of inhibiting at
least one PDE4 function comprising the step of contacting the PDE4 with a
compound of Formula I, as described herein. The cell phenotype, cell
proliferation, activity of PDE4, change in biochemical output produced by
active PDE4, expression of PDE4, or binding of PDE4 with a natural
binding partner may be monitored. Such methods may be modes of treatment
of disease, biological assays, cellular assays, biochemical assays, or
the like.

[0101]As used herein, the terms below have the meanings indicated.

[0102]When ranges of values are disclosed, and the notation "from n1
. . . to n2" is used, where n1 and n2 are the numbers,
then unless otherwise specified, this notation is intended to include the
numbers themselves and the range between them. This range may be integral
or continuous between and including the end values. By way of example,
the range "from 2 to 6 carbons" is intended to include two, three, four,
five, and six carbons, since carbons come in integer units. Compare, by
way of example, the range "from 1 to 3 μM (micromolar)," which is
intended to include 1 μM, 3 μM, and everything in between to any
number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999
μM, etc.).

[0103]The term "about," as used herein, is intended to qualify the
numerical values which it modifies, denoting such a value as variable
within a margin of error. When no particular margin of error, such as a
standard deviation to a mean value given in a chart or table of data, is
recited, the term "about" should be understood to mean that range which
would encompass the recited value and the range which would be included
by rounding up or down to that figure as well, taking into account
significant figures.

[0104]The term "acyl," as used herein, alone or in combination, refers to
a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,
heterocycloalkyl, or any other moiety were the atom attached to the
carbonyl is carbon. An "acetyl" group, which is a type of acyl, refers to
a --C(O)CH3 group. An "alkylcarbonyl" or "alkanoyl" group refers to
an alkyl group attached to the parent molecular moiety through a carbonyl
group. Examples of such groups include methylcarbonyl and ethylcarbonyl.
Examples of acyl groups include formyl, alkanoyl and aroyl.

[0105]The term "alkenyl," as used herein, alone or in combination, refers
to a straight-chain or branched-chain hydrocarbon radical having one or
more double bonds and containing from 2 to 20 carbon atoms. In certain
embodiments, said alkenyl will comprise from 2 to 6 carbon atoms. The
term "alkenylene" refers to a carbon-carbon double bond system attached
at two or more positions such as ethenylene [(--CH═CH--),(--C::C--)].
Examples of suitable alkenyl radicals include ethenyl, propenyl,
2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwise
specified, the term "alkenyl" may include "alkenylene" groups.

[0106]The term "alkoxy," as used herein, alone or in combination, refers
to an alkyl ether radical, wherein the term alkyl is as defined below.
Examples of suitable alkyl ether radicals include methoxy, ethoxy,
n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and
the like.

[0107]The term "alkyl," as used herein, alone or in combination, refers to
a straight-chain or branched-chain alkyl radical containing from 1 to 20
carbon atoms. In certain embodiments, said alkyl will comprise from 1 to
10 carbon atoms. In further embodiments, said alkyl will comprise from 1
to 6 carbon atoms. Alkyl groups may be optionally substituted as defined
herein. Examples of alkyl radicals include methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,
hexyl, octyl, noyl and the like. The term "alkylene," as used herein,
alone or in combination, refers to a saturated aliphatic group derived
from a straight or branched chain saturated hydrocarbon attached at two
or more positions, such as methylene (--CH2--). Unless otherwise
specified, the term "alkyl" may include "alkylene" groups.

[0108]The term "alkylamino," as used herein, alone or in combination,
refers to an alkyl group attached to the parent molecular moiety through
an amino group. Suitable alkylamino groups may be mono- or dialkylated,
forming groups such as, for example, N-methylamino, N-ethylamino,
N,N-dimethylamino, N,N-ethylmethylamino and the like.

[0109]The term "alkylidene," as used herein, alone or in combination,
refers to an alkenyl group in which one carbon atom of the carbon-carbon
double bond belongs to the moiety to which the alkenyl group is attached.

[0110]The term "alkylthio," as used herein, alone or in combination,
refers to an alkyl thioether (R--S--) radical wherein the term alkyl is
as defined above and wherein the sulfur may be singly or doubly oxidized.
Examples of suitable alkyl thioether radicals include methylthio,
ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio,
sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the
like.

[0111]The term "alkynyl," as used herein, alone or in combination, refers
to a straight-chain or branched chain hydrocarbon radical having one or
more triple bonds and containing from 2 to 20 carbon atoms. In certain
embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further
embodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term
"alkynylene" refers to a carbon-carbon triple bond attached at two
positions such as ethynylene (--C:::C--, --C≡C--). Examples of
alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,
butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.
Unless otherwise specified, the term "alkynyl" may include "alkynylene"
groups.

[0112]The terms "amido" and "carbamoyl," as used herein, alone or in
combination, refer to an amino group as described below attached to the
parent molecular moiety through a carbonyl group, or vice versa. The term
"C-amido" as used herein, alone or in combination, refers to a
--C(═O)--N(R)2 group with R as defined herein. The term
"N-amido" as used herein, alone or in combination, refers to a
RC(═O)N(R')-- group, with R and R' as defined herein. The term
"acylamino" as used herein, alone or in combination, embraces an acyl
group attached to the parent moiety through an amino group. An example of
an "acylamino" group is acetylamino (CH3C(O)NH--).

[0113]The term "amino," as used herein, alone or in combination, refers to
--N(R)(R') or --N.sup.+(R)(R')(R''), wherein R, R' and R'' are
independently selected from the group consisting of hydrogen, alkyl,
acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl,
any of which may themselves be optionally substituted.

[0114]The term "amino acid," as used herein, alone or in combination,
means a substituent of the form --NRCH(R')C(O)OH, wherein R is typically
hydrogen, but may be cyclized with N (for example, as in the case of the
amino acid proline), and R' is selected from the group consisting of
hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, amino, amido, cycloalkylalkyl, heterocycloalkylalkyl,
arylalkyl, heteroarylalkyl, aminoalkyl, amidoalkyl, hydroxyalkyl, thiol,
thioalkyl, alkylthioalkyl, and alkylthio, any of which may be optionally
substituted. The term "amino acid" includes all naturally occurring amino
acids as well as synthetic analogues.

[0115]The term "aryl," as used herein, alone or in combination, means a
carbocyclic aromatic system containing one, two or three rings wherein
such rings may be attached together in a pendent manner or may be fused.
The term "aryl" embraces aromatic radicals such as benzyl, phenyl,
naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl,
azulenyl, tetrahydronaphthyl, and biphenyl.

[0116]The term "arylalkenyl" or "aralkenyl," as used herein, alone or in
combination, refers to an aryl group attached to the parent molecular
moiety through an alkenyl group.

[0117]The term "arylalkoxy" or "aralkoxy," as used herein, alone or in
combination, refers to an aryl group attached to the parent molecular
moiety through an alkoxy group.

[0118]The term "arylalkyl" or "aralkyl," as used herein, alone or in
combination, refers to an aryl group attached to the parent molecular
moiety through an alkyl group.

[0119]The term "arylalkynyl" or "aralkynyl," as used herein, alone or in
combination, refers to an aryl group attached to the parent molecular
moiety through an alkynyl group.

[0120]The term "arylalkanoyl" or "aralkanoyl" or "aroyl," as used herein,
alone or in combination, refers to an acyl radical derived from an
aryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl,
phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,
(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0121]The term aryloxy as used herein, alone or in combination, refers to
an aryl group attached to the parent molecular moiety through an oxy.

[0122]The terms "benzo" and "benz," as used herein, alone or in
combination, refer to the divalent radical C6H4═ derived
from benzene. Examples include benzothiophene and benzimidazole.

[0123]The term "carbamate," as used herein, alone or in combination,
refers to an ester of carbamic acid (--NHCOO--) which may be attached to
the parent molecular moiety from either the nitrogen or acid end, and
which may be optionally substituted as defined herein.

[0124]The term "O-carbamyl" as used herein, alone or in combination,
refers to a --OC(O)NRR', group, with R and R' as defined herein.

[0125]The term "N-carbamyl" as used herein, alone or in combination,
refers to a ROC(O)NR'-- group, with R and R' as defined herein.

[0126]The term "carbonyl," as used herein, when alone includes formyl
[--C(O)H] and in combination is a --C(O)-- group.

[0127]The term "carboxyl" or "carboxyl," as used herein, refers to
--C(O)OH, O-carboxy, C-carboxy, or the corresponding "carboxylate" anion,
such as is in a carboxylic acid salt. An "O-carboxy" group refers to a
RC(O)O-- group, where R is as defined herein. A "C-carboxy" group refers
to a --C(O)OR groups where R is as defined herein.

[0128]The term "cyano," as used herein, alone or in combination, refers to
--CN.

[0129]The term "cycloalkyl," or, alternatively, "carbocycle," as used
herein, alone or in combination, refers to a saturated or partially
saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each
cyclic moiety contains from 3 to 12 carbon atom ring members and which
may optionally be a benzo fused ring system which is optionally
substituted as defined herein. In certain embodiments, said cycloalkyl
will comprise from 5 to 7 carbon atoms. Examples of such cycloalkyl
radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and the
like. "Bicyclic" and "tricyclic" as used herein are intended to include
both fused ring systems, such as decahydronaphthalene,
octahydronaphthalene as well as the multicyclic (multicentered) saturated
or partially unsaturated type. The latter type of isomer is exemplified
in general by, bicyclo[1,1,1]pentane, camphor, adamantane, and bicyclo
[3,2,1]octane.

[0130]The term "ester," as used herein, alone or in combination, refers to
a carboxyl group bridging two moieties linked at carbon atoms.

[0131]The term "ether," as used herein, alone or in combination, typically
refers to an oxy group bridging two moieties linked at carbon atoms.
"Ether" may also include polyethers, such as, for example,
--RO(CH2)2O(CH2)2O(CH2)2OR',
--RO(CH2)2O(CH2)2OR', --RO(CH2)2OR', and
--RO(CH2)2OH.

[0132]The term "halo," or "halogen," as used herein, alone or in
combination, refers to fluorine, chlorine, bromine, or iodine.

[0133]The term "haloalkoxy," as used herein, alone or in combination,
refers to a haloalkyl group attached to the parent molecular moiety
through an oxygen atom.

[0134]The term "haloalkyl," as used herein, alone or in combination,
refers to an alkyl radical having the meaning as defined above wherein
one or more hydrogens are replaced with a halogen. Specifically embraced
are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A
monohaloalkyl radical, for one example, may have an iodo, bromo, chloro
or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may
have two or more of the same halo atoms or a combination of different
halo radicals. Examples of haloalkyl radicals include fluoromethyl,
difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,
trichloromethyl, pentafluoroethyl, heptafluoropropyl,
difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,
difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers
to a haloalkyl group attached at two or more positions. Examples include
fluoromethylene (--CFH--), difluoromethylene (--CF2--),
chloromethylene (--CHCl--) and the like.

[0135]The term "heteroalkyl," as used herein, alone or in combination,
refers to a stable straight or branched chain, or cyclic hydrocarbon
radical, or combinations thereof, fully saturated or containing from 1 to
3 degrees of unsaturation, consisting of the stated number of carbon
atoms and from one to three heteroatoms selected from the group
consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may
optionally be oxidized and the nitrogen heteroatom may optionally be
quaternized. The heteroatom(s) O, N and S may be placed at any interior
position of the heteroalkyl group. Up to two heteroatoms may be
consecutive, such as, for example, --CH2--NH--OCH3. The term
heteroalkyl may include ethers.

[0137]The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as
used herein, alone or in combination, each refer to a saturated,
partially unsaturated, or fully unsaturated monocyclic, bicyclic, or
tricyclic heterocyclic radical containing at least one heteroatom as ring
members, wherein each said heteroatom may be independently selected from
the group consisting of nitrogen, oxygen, and sulfur In certain
embodiments, said heterocycloalkyl will comprise from 1 to 4 heteroatoms
as ring members. In further embodiments, said heterocycloalkyl will
comprise from 1 to 2 heteroatoms ring members. In certain embodiments,
said heterocycloalkyl will comprise from 3 to 8 ring members in each
ring. In further embodiments, said heterocycloalkyl will comprise from 3
to 7 ring members in each ring. In yet further embodiments, said
heterocycloalkyl will comprise from 5 to 6 ring members in each ring.
"Heterocycloalkyl" and "heterocycle" are intended to include sugars,
sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and
carbocyclic fused and benzo fused ring systems; additionally, both terms
also include systems where a heterocycle ring is fused to an aryl group,
as defined herein, or an additional heterocycle group. Examples of
heterocycloalkyl groups include aziridinyl, azetidinyl,
1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl,
dihydrocinnolinyl, dihydrobenzodioxinyl,
dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,
dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,
isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl,
tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The
heterocycloalkyl groups may be optionally substituted unless specifically
prohibited.

[0138]The term "hydrazinyl" as used herein, alone or in combination,
refers to two amino groups joined by a single bond, i.e., --N--N--.

[0139]The term "hydroxamic acid" as used herein, refers to
--C(O)ON(R)O(R'), wherein R and R' are as defined herein, or the
corresponding "hydroxamate" anion, including any corresponding hydroxamic
acid salt.

[0140]The term "hydroxy," as used herein, alone or in combination, refers
to --OH.

[0141]The term "hydroxyalkyl," as used herein, alone or in combination,
refers to a hydroxy group attached to the parent molecular moiety through
an alkyl group.

[0142]The term "imino," as used herein, alone or in combination, refers to
═N--.

[0143]The term "iminohydroxy," as used herein, alone or in combination,
refers to ═N(OH) and ═N--O--.

[0147]The term "lower," as used herein, alone or in combination, means
containing from 1 to and including 6 carbon atoms.

[0148]The term "mercaptyl" as used herein, alone or in combination, refers
to an RS-- group, where R is as defined herein.

[0149]The term "nitro," as used herein, alone or in combination, refers to
--NO2.

[0150]The terms "oxy" or "oxa," as used herein, alone or in combination,
refer to --O--.

[0151]The term "oxo," as used herein, alone or in combination, refers to
═O.

[0152]The term "perhaloalkoxy" refers to an alkoxy group where all of the
hydrogen atoms are replaced by halogen atoms.

[0153]The term "perhaloalkyl" as used herein, alone or in combination,
refers to an alkyl group where all of the hydrogen atoms are replaced by
halogen atoms.

[0154]The term "phosphoamide" as used herein, alone or in combination,
refers to a phosphate group [(OH)2P(O)O--] in which one or more of
the hydroxyl groups has been replaced by nitrogen, amino, or amido.

[0155]The term "phosphonate" as used herein, alone or in combination,
refers to a group of the form ROP(OR)(OR')O-- wherein R and R' are
selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl,
aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may
themselves be optionally substituted. "Phosphonate" includes "phosphate
[(OH)2P(O)O--] and related phosphoric acid anions which may form
salts.

[0156]The terms "sulfonate," "sulfonic acid," and "sulfonic," as used
herein, alone or in combination, refer the --SO3H group and its
anion as the sulfonic acid is used in salt formation.

[0157]The term "sulfanyl," as used herein, alone or in combination, refers
to --S--.

[0158]The term "sulfinyl," as used herein, alone or in combination, refers
to --S(O)--.

[0159]The term "sulfonyl," as used herein, alone or in combination, refers
to --S(O)2--.

[0160]The term "N-sulfonamido" refers to a RS(═O)2NR'-group with
R and R' as defined herein.

[0161]The term "S-sulfonamido" refers to a --S(═O)2NRR', group,
with R and R' as defined herein.

[0162]The terms "thia" and "thio," as used herein, alone or in
combination, refer to a --S-- group or an ether wherein the oxygen is
replaced with sulfur. The oxidized derivatives of the thio group, namely
sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0163]The term "thiol," as used herein, alone or in combination, refers to
an --SH group.

[0164]The term "thiocarbonyl," as used herein, when alone includes
thioformyl --C(S)H and in combination is a --C(S)-- group.

[0165]The term "N-thiocarbamyl" refers to an ROC(S)NR'-group, with R and
R' as defined herein.

[0166]The term "O-thiocarbamyl" refers to a --OC(S)NRR', group with R and
R' as defined herein.

[0167]The term "thiocyanato" refers to a --CNS group.

[0168]The term "trihalomethanesulfonamido" refers to a
X3CS(O)2NR-- group with X is a halogen and R as defined herein.

[0169]The term "trihalomethanesulfonyl" refers to a X3CS(O)2--
group where X is a halogen.

[0170]The term "trihalomethoxy" refers to a X3CO-- group where X is a
halogen.

[0171]The term "trisubstituted silyl," as used herein, alone or in
combination, refers to a silicone group substituted at its three free
valences with groups as listed herein under the definition of substituted
amino. Examples include trimethysilyl, tert-butyldimethylsilyl,
triphenylsilyl and the like.

[0172]Any definition herein may be used in combination with any other
definition to describe a composite structural group. By convention, the
trailing element of any such definition is that which attaches to the
parent moiety. For example, the composite group alkylamido would
represent an alkyl group attached to the parent molecule through an amido
group, and the term alkoxyalkyl would represent an alkoxy group attached
to the parent molecule through an alkyl group.

[0173]When a group is defined to be "null," what is meant is that said
group is absent. A "null" group occurring between two other group may
also be understood to be a collapsing of flanking groups. For example, if
in --(CH2)sG1G2G3, the element G2 were
null, said group would become --(CH2)sG1G3.

[0174]The term "optionally substituted" means the anteceding group may be
substituted or unsubstituted. When substituted, the substituents of an
"optionally substituted" group may include, without limitation, one or
more substituents independently selected from the following groups or a
particular designated set of groups, alone or in combination: lower
alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,
lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower
haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,
phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower
acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,
lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower
alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower
haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic
acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3,
CO2CH3, CO2H, pyridinyl, thiophene, furanyl, lower
carbamate, and lower urea. Two substituents may be joined together to
form a fused five-, six-, or seven-membered carbocyclic or heterocyclic
ring consisting of zero to three heteroatoms, for example forming
methylenedioxy or ethylenedioxy. An optionally substituted group may be
unsubstituted (e.g., --CH2CH3), fully substituted (e.g.,
--CF2CF3), monosubstituted (e.g., --CH2CH2F) or
substituted at a level anywhere in-between fully substituted and
monosubstituted (e.g., --CH2CF3). Where substituents are
recited without qualification as to substitution, both substituted and
unsubstituted forms are encompassed. Where a substituent is qualified as
"substituted," the substituted form is specifically intended.
Additionally, different sets of optional substituents to a particular
moiety may be defined as needed; in these cases, the optional
substitution will be as defined, often immediately following the phrase,
"optionally substituted with."

[0175]The term R or the term R', appearing by itself and without a number
designation, unless otherwise defined, refers to a moiety selected from
the group consisting of hydrogen, hydroxyl, halogen, alkyl, cycloalkyl,
heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be
optionally substituted. Such R and R' groups should be understood to be
optionally substituted as defined herein. Whether an R group has a number
designation or not, every R group, including R, R' and Rn where
n=(1, 2, 3, . . . n), every substituent, and every term should be
understood to be independent of every other in terms of selection from a
group. Should any variable, substituent, or term (e.g. aryl, heterocycle,
R, etc.) occur more than one time in a formula or generic structure, its
definition at each occurrence is independent of the definition at every
other occurrence. Those of skill in the art will further recognize that
certain groups may be attached to a parent molecule or may occupy a
position in a chain of elements from either end as written. Thus, by way
of example only, an unsymmetrical group such as --C(O)N(R)-- may be
attached to the parent moiety at either the carbon or the nitrogen.

[0176]Asymmetric centers exist in the compounds of the present invention.
These centers are designated by the symbols "R" or "S," depending on the
configuration of substituents around the chiral carbon atom. It should be
understood that the invention encompasses all stereochemical isomeric
forms, including diastereomeric, enantiomeric, and epimeric forms, as
well as d-isomers and 1-isomers, and mixtures thereof. Individual
stereoisomers of compounds can be prepared synthetically from
commercially available starting materials which contain chiral centers or
by preparation of mixtures of enantiomeric products followed by
separation such as conversion to a mixture of diastereomers followed by
separation or recrystallization, chromatographic techniques, direct
separation of enantiomers on chiral chromatographic columns, or any other
appropriate method known in the art. Starting compounds of particular
stereochemistry are either commercially available or can be made and
resolved by techniques known in the art. Additionally, the compounds of
the present invention may exist as geometric isomers. The present
invention includes all cis, trans, syn, anti, entgegen (E), and zusammen
(Z) isomers as well as the appropriate mixtures thereof. Additionally,
compounds may exist as tautomers, including keto-enol tautomers; all
tautomeric isomers are provided by this invention. By way of example, the
following pair of tautomers illustrate how both forms are contemplated
herein:

##STR00006##

Additionally, the compounds of the present invention can exist in
unsolvated as well as solvated forms with pharmaceutically acceptable
solvents such as water, ethanol, and the like. In general, the solvated
forms are considered equivalent to the unsolvated forms for the purposes
of the present invention.

[0177]The term "bond" refers to a covalent linkage between two atoms, or
two moieties when the atoms joined by the bond are considered to be part
of larger substructure. A bond may be single, double, or triple unless
otherwise specified. A dashed line between two atoms in a drawing of a
molecule indicates that an additional bond may be present or absent at
that position.

[0178]The term "disease" as used herein is intended to be generally
synonymous, and is used interchangeably with, the terms "disorder" and
"condition" (as in medical condition), in that all reflect an abnormal
condition of the body or of one of its parts that impairs normal
functioning and is typically manifested by distinguishing signs and
symptoms.

[0179]The term "combination therapy" means the administration of two or
more therapeutic agents to treat a therapeutic condition or disorder
described in the present disclosure. Such administration encompasses
co-administration of these therapeutic agents in a substantially
simultaneous manner, such as in a single capsule having a fixed ratio of
active ingredients or in multiple, separate capsules for each active
ingredient. In addition, such administration also encompasses use of each
type of therapeutic agent in a sequential manner. In either case, the
treatment regimen will provide beneficial effects of the drug combination
in treating the conditions or disorders described herein.

[0180]"PDE4 inhibitor" is used herein to refer to a compound that exhibits
an IC50 with respect to PDE4 activity of no more than about 100
μM and more typically not more than about 50 μM, as measured in the
PDE4 assay described generally hereinbelow. "IC50" is that
concentration of inhibitor which reduces the activity of an enzyme (e.g.,
PDE4) to half-maximal level. Certain representative compounds of the
present invention have been discovered to exhibit inhibition against
PDE4. In certain embodiments, compounds will exhibit an IC50 with
respect to PDE4 of no more than about 10 μM; in further embodiments,
compounds will exhibit an IC50 with respect to PDE4 of no more than
about 5 μM; in yet further embodiments, compounds will exhibit an
IC50 with respect to PDE4 of not more than about 1 μM, as
measured in the PDE4 assay described herein. In yet further embodiments,
compounds will exhibit an IC50 with respect to PDE4 of not more than
about 200 nM.

[0181]The phrase "therapeutically effective" is intended to qualify the
amount of active ingredients used in the treatment of a disease or
disorder. This amount will achieve the goal of reducing or eliminating
the said disease or disorder.

[0182]As used herein, reference to "treatment" of a patient is intended to
include prophylaxis. The term "patient" means all mammals including
humans. Examples of patients include humans, cows, dogs, cats, goats,
sheep, pigs, and rabbits. Preferably, the patient is a human.

[0183]The term "prodrug" refers to a compound that is made more active in
vivo. Certain of the present compounds can also exist as prodrugs, as
described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,
Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.
Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds
described herein are structurally modified forms of the compound that
readily undergo chemical changes under physiological conditions to
provide the compound. Additionally, prodrugs can be converted to the
compound by chemical or biochemical methods in an ex vivo environment.
For example, prodrugs can be slowly converted to a compound when placed
in a transdermal patch reservoir with a suitable enzyme or chemical
reagent. Prodrugs are often useful because, in some situations, they may
be easier to administer than the compound, or parent drug. They may, for
instance, be bioavailable by oral administration whereas the parent drug
is not. The prodrug may also have improved solubility in pharmaceutical
compositions over the parent drug. A wide variety of prodrug derivatives
are known in the art, such as those that rely on hydrolytic cleavage or
oxidative activation of the prodrug. An example, without limitation, of a
prodrug would be a compound which is administered as an ester (the
"prodrug"), but then is metabolically hydrolyzed to the carboxylic acid,
the active entity. Additional examples include peptidyl derivatives of a
compound. The term "therapeutically acceptable prodrug," refers to those
prodrugs or zwitterions which are suitable for use in contact with the
tissues of patients without undue toxicity, irritation, and allergic
response, are commensurate with a reasonable benefit/risk ratio, and are
effective for their intended use.

[0184]The compounds of the present invention can exist as therapeutically
acceptable salts. The present invention includes compounds listed above
in the form of salts, including acid addition salts. Suitable salts
include those formed with both organic and inorganic acids. Such acid
addition salts will normally be pharmaceutically acceptable. However,
salts of non-pharmaceutically acceptable salts may be of utility in the
preparation and purification of the compound in question. Basic addition
salts may also be formed and be pharmaceutically acceptable. For a more
complete discussion of the preparation and selection of salts, refer to
Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich.
Wiley-VCHA, Zurich, Switzerland, 2002).

[0185]The term "therapeutically acceptable salt," as used herein,
represents salts or zwitterionic forms of the compounds of the present
invention which are water or oil-soluble or dispersible and
therapeutically acceptable as defined herein. The salts can be prepared
during the final isolation and purification of the compounds or
separately by reacting the appropriate compound in the form of the free
base with a suitable acid. Representative acid addition salts include
acetate, adipate, alginate, L-ascorbate, aspartate, benzoate,
benzenesulfonate (besylate), bisulfate, butyrate, camphorate,
camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate,
glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate,
hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate,
DL-mandelate, mesitylenesulfonate, methanesulfonate,
naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,
pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate,
picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate,
tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate,
glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and
undecanoate. Also, basic groups in the compounds of the present invention
can be quaternized with methyl, ethyl, propyl, and butyl chlorides,
bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates;
decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and
benzyl and phenethyl bromides. Examples of acids which can be employed to
form therapeutically acceptable addition salts include inorganic acids
such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic
acids such as oxalic, maleic, succinic, and citric. Salts can also be
formed by coordination of the compounds with an alkali metal or alkaline
earth ion. Hence, the present invention contemplates sodium, potassium,
magnesium, and calcium salts of the compounds disclosed herein, and the
like.

[0186]Basic addition salts can be prepared during the final isolation and
purification of the compounds by reacting a carboxyl group with a
suitable base such as the hydroxide, carbonate, or bicarbonate of a metal
cation or with ammonia or an organic primary, secondary, or tertiary
amine. The cations of therapeutically acceptable salts include lithium,
sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic
quaternary amine cations such as ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine, tributylamine, pyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,
1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative
organic amines useful for the formation of base addition salts include
ethylenediamine, ethanolamine, diethanolamine, piperidine, and
piperazine.

[0187]While it may be possible for the compounds of the subject invention
to be administered as the raw chemical, it is also possible to present
them as a pharmaceutical formulation. Accordingly, provided herein are
pharmaceutical formulations which comprise one or more of certain
compounds of the present invention, or one or more pharmaceutically
acceptable salts, esters, prodrugs, amides, or solvates thereof, together
with one or more pharmaceutically acceptable carriers thereof and
optionally one or more other therapeutic ingredients. The carrier(s) must
be "acceptable" in the sense of being compatible with the other
ingredients of the formulation and not deleterious to the recipient
thereof. Proper formulation is dependent upon the route of administration
chosen. Any of the well-known techniques, carriers, and excipients may be
used as suitable and as understood in the art; e.g., in Remington's
Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein
may be manufactured in any manner known in the art, e.g., by means of
conventional mixing, dissolving, granulating, dragee-making, levigating,
emulsifying, encapsulating, entrapping or compression processes.

[0188]The formulations include those suitable for oral, parenteral
(including subcutaneous, intradermal, intramuscular, intravenous,
intraarticular, and intramedullary), intraperitoneal, transmucosal,
transdermal, rectal and topical (including dermal, buccal, sublingual and
intraocular) administration although the most suitable route may depend
upon for example the condition and disorder of the recipient. The
formulations may conveniently be presented in unit dosage form and may be
prepared by any of the methods well known in the art of pharmacy.
Typically, these methods include the step of bringing into association a
compound of the subject invention or a pharmaceutically acceptable salt,
ester, amide, prodrug or solvate thereof ("active ingredient") with the
carrier which constitutes one or more accessory ingredients. In general,
the formulations are prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or finely divided
solid carriers or both and then, if necessary, shaping the product into
the desired formulation.

[0189]Formulations of the present invention suitable for oral
administration may be presented as discrete units such as capsules,
cachets or tablets each containing a predetermined amount of the active
ingredient; as a powder or granules; as a solution or a suspension in an
aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid
emulsion or a water-in-oil liquid emulsion. The active ingredient may
also be presented as a bolus, electuary or paste.

[0190]Pharmaceutical preparations which can be used orally include
tablets, push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
Tablets may be made by compression or molding, optionally with one or
more accessory ingredients. Compressed tablets may be prepared by
compressing in a suitable machine the active ingredient in a free-flowing
form such as a powder or granules, optionally mixed with binders, inert
diluents, or lubricating, surface active or dispersing agents. Molded
tablets may be made by molding in a suitable machine a mixture of the
powdered compound moistened with an inert liquid diluent. The tablets may
optionally be coated or scored and may be formulated so as to provide
slow or controlled release of the active ingredient therein. All
formulations for oral administration should be in dosages suitable for
such administration. The push-fit capsules can contain the active
ingredients in admixture with filler such as lactose, binders such as
starches, and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds may be
dissolved or suspended in suitable liquids, such as fatty oils, liquid
paraffin, or liquid polyethylene glycols. In addition, stabilizers may be
added. Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions may be used, which may optionally
contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,
polyethylene glycol, and/or titanium dioxide, lacquer solutions, and
suitable organic solvents or solvent mixtures. Dyestuffs or pigments may
be added to the tablets or dragee coatings for identification or to
characterize different combinations of active compound doses.

[0191]The compounds may be formulated for parenteral administration by
injection, e.g., by bolus injection or continuous infusion. Formulations
for injection may be presented in unit dosage form, e.g., in ampoules or
in multi-dose containers, with an added preservative. The compositions
may take such forms as suspensions, solutions or emulsions in oily or
aqueous vehicles, and may contain formulatory agents such as suspending,
stabilizing and/or dispersing agents. The formulations may be presented
in unit-dose or multi-dose containers, for example sealed ampoules and
vials, and may be stored in powder form or in a freeze-dried
(lyophilized) condition requiring only the addition of the sterile liquid
carrier, for example, saline or sterile pyrogen-free water, immediately
prior to use. Extemporaneous injection solutions and suspensions may be
prepared from sterile powders, granules and tablets of the kind
previously described.

[0192]Formulations for parenteral administration include aqueous and
non-aqueous (oily) sterile injection solutions of the active compounds
which may contain antioxidants, buffers, bacteriostats and solutes which
render the formulation isotonic with the blood of the intended recipient;
and aqueous and non-aqueous sterile suspensions which may include
suspending agents and thickening agents. Suitable lipophilic solvents or
vehicles include fatty oils such as sesame oil, or synthetic fatty acid
esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous
injection suspensions may contain substances which increase the viscosity
of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or
dextran. Optionally, the suspension may also contain suitable stabilizers
or agents which increase the solubility of the compounds to allow for the
preparation of highly concentrated solutions.

[0193]In addition to the formulations described previously, the compounds
may also be formulated as a depot preparation. Such long acting
formulations may be administered by implantation (for example
subcutaneously or intramuscularly) or by intramuscular injection. Thus,
for example, the compounds may be formulated with suitable polymeric or
hydrophobic materials (for example as an emulsion in an acceptable oil)
or ion exchange resins, or as sparingly soluble derivatives, for example,
as a sparingly soluble salt.

[0194]For buccal or sublingual administration, the compositions may take
the form of tablets, lozenges, pastilles, or gels formulated in
conventional manner. Such compositions may comprise the active ingredient
in a flavored basis such as sucrose and acacia or tragacanth.

[0195]The compounds may also be formulated in rectal compositions such as
suppositories or retention enemas, e.g., containing conventional
suppository bases such as cocoa butter, polyethylene glycol, or other
glycerides.

[0196]Certain compounds of the present invention may be administered
topically, that is by non-systemic administration. This includes the
application of a compound of the present invention externally to the
epidermis or the buccal cavity and the instillation of such a compound
into the ear, eye and nose, such that the compound does not significantly
enter the blood stream. In contrast, systemic administration refers to
oral, intravenous, intraperitoneal and intramuscular administration.

[0197]Formulations suitable for topical administration include liquid or
semi-liquid preparations suitable for penetration through the skin to the
site of inflammation such as gels, liniments, lotions, creams, ointments
or pastes, and drops suitable for administration to the eye, ear or nose.
The active ingredient for topical administration may comprise, for
example, from 0.001% to 10% w/w (by weight) of the formulation. In
certain embodiments, the active ingredient may comprise as much as 10%
w/w. In other embodiments, it may comprise less than 5% w/w. In certain
embodiments, the active ingredient may comprise from 2% w/w to 5% w/w. In
other embodiments, it may comprise from 0.1% to 1% w/w of the
formulation.

[0198]Gels for topical or transdermal administration may comprise,
generally, a mixture of volatile solvents, nonvolatile solvents, and
water. In certain embodiments, the volatile solvent component of the
buffered solvent system may include lower (C1-C6) alkyl alcohols,
lower alkyl glycols and lower glycol polymers. In further embodiments,
the volatile solvent is ethanol. The volatile solvent component is
thought to act as a penetration enhancer, while also producing a cooling
effect on the skin as it evaporates. The nonvolatile solvent portion of
the buffered solvent system is selected from lower alkylene glycols and
lower glycol polymers. In certain embodiments, propylene glycol is used.
The nonvolatile solvent slows the evaporation of the volatile solvent and
reduces the vapor pressure of the buffered solvent system. The amount of
this nonvolatile solvent component, as with the volatile solvent, is
determined by the pharmaceutical compound or drug being used. When too
little of the nonvolatile solvent is in the system, the pharmaceutical
compound may crystallize due to evaporation of volatile solvent, while an
excess may result in a lack of bioavailability due to poor release of
drug from solvent mixture. The buffer component of the buffered solvent
system may be selected from any buffer commonly used in the art; in
certain embodiments, water is used. A common ratio of ingredients is
about 20% of the nonvolatile solvent, about 40% of the volatile solvent,
and about 40% water. There are several optional ingredients which can be
added to the topical composition. These include, but are not limited to,
chelators and gelling agents. Appropriate gelling agents can include, but
are not limited to, semisynthetic cellulose derivatives (such as
hydroxypropylmethylcellulose) and synthetic polymers, and cosmetic
agents.

[0199]Lotions include those suitable for application to the skin or eye.
An eye lotion may comprise a sterile aqueous solution optionally
containing a bactericide and may be prepared by methods similar to those
for the preparation of drops. Lotions or liniments for application to the
skin may also include an agent to hasten drying and to cool the skin,
such as an alcohol or acetone, and/or a moisturizer such as glycerol or
an oil such as castor oil or arachis oil.

[0200]Creams, ointments or pastes are semi-solid formulations of the
active ingredient for external application. They may be made by mixing
the active ingredient in finely-divided or powdered form, alone or in
solution or suspension in an aqueous or non-aqueous fluid, with the aid
of suitable machinery, with a greasy or non-greasy base. The base may
comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,
beeswax, a metallic soap; a mucilage; an oil of natural origin such as
almond, corn, arachis, castor or olive oil; wool fat or its derivatives
or a fatty acid such as stearic or oleic acid together with an alcohol
such as propylene glycol or a macrogel. The formulation may incorporate
any suitable surface active agent such as an anionic, cationic or
non-ionic surfactant such as a sorbitan ester or a polyoxyethylene
derivative thereof. Suspending agents such as natural gums, cellulose
derivatives or inorganic materials such as silicaceous silicas, and other
ingredients such as lanolin, may also be included.

[0201]Drops may comprise sterile aqueous or oily solutions or suspensions
and may be prepared by dissolving the active ingredient in a suitable
aqueous solution of a bactericidal and/or fungicidal agent and/or any
other suitable preservative, and, in certain embodiments, including a
surface active agent. The resulting solution may then be clarified by
filtration, transferred to a suitable container which is then sealed and
sterilized by autoclaving or maintaining at 98-100° C. for half an
hour. Alternatively, the solution may be sterilized by filtration and
transferred to the container by an aseptic technique. Examples of
bactericidal and fungicidal agents suitable for inclusion in the drops
are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride
(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the
preparation of an oily solution include glycerol, diluted alcohol and
propylene glycol.

[0202]Formulations for topical administration in the mouth, for example
buccally or sublingually, include lozenges comprising the active
ingredient in a flavored basis such as sucrose and acacia or tragacanth,
and pastilles comprising the active ingredient in a basis such as gelatin
and glycerin or sucrose and acacia.

[0203]For administration by inhalation, compounds may be conveniently
delivered from an insufflator, nebulizer pressurized packs or other
convenient means of delivering an aerosol spray. Pressurized packs may
comprise a suitable propellant such as dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
other suitable gas. In the case of a pressurized aerosol, the dosage unit
may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation or insufflation, the
compounds according to the invention may take the form of a dry powder
composition, for example a powder mix of the compound and a suitable
powder base such as lactose or starch. The powder composition may be
presented in unit dosage form, in for example, capsules, cartridges,
gelatin or blister packs from which the powder may be administered with
the aid of an inhalator or insufflator.

[0204]Preferred unit dosage formulations are those containing an effective
dose, as herein below recited, or an appropriate fraction thereof, of the
active ingredient.

[0205]It should be understood that in addition to the ingredients
particularly mentioned above, the formulations described above may
include other agents conventional in the art having regard to the type of
formulation in question, for example those suitable for oral
administration may include flavoring agents.

[0206]Compounds may be administered orally or via injection at a dose of
from 0.1 to 500 mg/kg per day. The dose range for adult humans is
generally from 5 mg to 2 g/day. Tablets or other forms of presentation
provided in discrete units may conveniently contain an amount of one or
more compounds which is effective at such dosage or as a multiple of the
same, for instance, units containing 5 mg to 500 mg, usually around 10 mg
to 200 mg.

[0207]The amount of active ingredient that may be combined with the
carrier materials to produce a single dosage form will vary depending
upon the host treated and the particular mode of administration.

[0208]The compounds can be administered in various modes, e.g. orally,
topically, or by injection. The precise amount of compound administered
to a patient will be the responsibility of the attendant physician. The
specific dose level for any particular patient will depend upon a variety
of factors including the activity of the specific compound employed, the
age, body weight, general health, sex, diets, time of administration,
route of administration, rate of excretion, drug combination, the precise
disorder being treated, and the severity of the indication or condition
being treated. Also, the route of administration may vary depending on
the condition and its severity.

[0209]In certain instances, it may be appropriate to administer at least
one of the compounds described herein (or a pharmaceutically acceptable
salt, ester, or prodrug thereof) in combination with another therapeutic
agent. By way of example only, if one of the side effects experienced by
a patient upon receiving one of the compounds herein is hypertension,
then it may be appropriate to administer an anti-hypertensive agent in
combination with the initial therapeutic agent. Or, by way of example
only, the therapeutic effectiveness of one of the compounds described
herein may be enhanced by administration of an adjuvant (i.e., by itself
the adjuvant may only have minimal therapeutic benefit, but in
combination with another therapeutic agent, the overall therapeutic
benefit to the patient is enhanced). Or, by way of example only, the
benefit of experienced by a patient may be increased by administering one
of the compounds described herein with another therapeutic agent (which
also includes a therapeutic regimen) that also has therapeutic benefit.
By way of example only, in a treatment for diabetes involving
administration of one of the compounds described herein, increased
therapeutic benefit may result by also providing the patient with another
therapeutic agent for diabetes. In any case, regardless of the disease,
disorder or condition being treated, the overall benefit experienced by
the patient may simply be additive of the two therapeutic agents or the
patient may experience a synergistic benefit.

[0210]In any case, the multiple therapeutic agents (at least one of which
is a compound of the present invention) may be administered in any order
or even simultaneously. If simultaneously, the multiple therapeutic
agents may be provided in a single, unified form, or in multiple forms
(by way of example only, either as a single pill or as two separate
pills). One of the therapeutic agents may be given in multiple doses, or
both may be given as multiple doses. If not simultaneous, the timing
between the multiple doses may be any duration of time ranging from a few
minutes to four weeks.

[0211]Thus, in another aspect, the present invention provides methods for
treating PDE4-mediated disorders in a human or animal subject in need of
such treatment comprising administering to said subject an amount of a
compound of the present invention effective to reduce or prevent said
disorder in the subject in combination with at least one additional agent
for the treatment of said disorder that is known in the art. In a related
aspect, the present invention provides therapeutic compositions
comprising at least one compound of the present invention in combination
with one or more additional agents for the treatment of PDE4-mediated
disorders.

[0212]Compounds of the subject invention may be useful in treating
PDE4-mediated disease, disorders and conditions. In certain embodiments,
said compounds may find use in treating acute and chronic pain and
inflammation. The compounds of the present invention may be useful to
treat patients with neuropathy, neuropathic pain, or inflammatory pain
such as reflex sympathetic dystrophy/causalgia (nerve injury), peripheral
neuropathy (including diabetic neuropathy), intractable cancer pain,
complex regional pain syndrome, and entrapment neuropathy (carpel tunnel
syndrome). The compounds may also be useful in the treatment of pain
associated with acute herpes zoster (shingles), postherpetic neuralgia
(PHN), and associated pain syndromes such as ocular pain. The compounds
may further be useful as analgesics in the treatment of pain such as
surgical analgesia, or as an antipyretic for the treatment of fever. Pain
indications include, but are not limited to, post-surgical pain for
various surgical procedures including post-cardiac surgery, dental
pain/dental extraction, pain resulting from cancer, muscular pain,
mastalgia, pain resulting from dermal injuries, lower back pain,
headaches of various etiologies, including migraine, and the like. The
compounds may also be useful for the treatment of pain-related disorders
such as tactile allodynia and hyperalgesia. The pain may be somatogenic
(either nociceptive or neuropathic), acute and/or chronic. The PDE4
inhibitors of the subject invention may also be useful in conditions
where NSAIDs, morphine or fentanyl opiates and/or other opioid analgesics
would traditionally be administered.

[0213]Furthermore, compounds of the subject invention may be used in the
treatment or prevention of opiate tolerance in patients needing
protracted opiate analgesics, and benzodiazepine tolerance in patients
taking benzodiazepines, and other addictive behavior, for example,
nicotine addiction, alcoholism, and eating disorders. Moreover, the
compounds and methods of the present invention may be useful in the
treatment or prevention of drug withdrawal symptoms, for example
treatment or prevention of symptoms of withdrawal from opiate, alcohol,
or tobacco addiction.

[0214]In addition, compounds of the subject invention may be used to treat
insulin resistance and other metabolic disorders such as atherosclerosis
that are typically associated with an exaggerated inflammatory signaling.

[0216]Other disorders or conditions which may be treated by the compounds
of the present invention include inflammation and related disorders. The
compounds of the present invention may be useful as anti-inflammatory
agents with the additional benefit of having significantly less harmful
side effects. The compounds may be useful to treat arthritis, including
but not limited to rheumatoid arthritis, spondyloarthropathies, gouty
arthritis, osteoarthritis, juvenile arthritis, acute rheumatic arthritis,
enteropathic arthritis, neuropathic arthritis, psoriatic arthritis,
reactive arthritis (Reiter's syndrome), and pyogenic arthritis, and
autoimmune diseases, including systemic lupus erythematosus, hemolytic
syndromes, autoimmune hepatitis, autoimmune neuropathy, vitiglio
(autoimmune thyroiditis), Hashimoto's thyroiditis, anemias, myositis
including polymyositis, alopecia greata, Goodpasture's syndrome,
hypophytis, and pulmonary fibrosis.

[0217]The compounds may also be useful in treating osteoporosis and other
related bone disorders.

[0218]These compounds may also be used to treat gastrointestinal
conditions such as reflux esophagitis, diarrhea, inflammatory bowel
disease, Crohn's disease, gastritis, irritable bowel syndrome, Graves'
disease (hyperthyroidism), necrotizing enterocolitis, and ulcerative
colitis. The compounds may also be used in the treatment of pulmonary
inflammation, such as that associated with viral infections and cystic
fibrosis.

[0222]The compounds of the subject invention may also be useful for the
treatment of certain diseases and disorders of the nervous system.
Central nervous system disorders in which PDE4 inhibition may be useful
include cortical dementias including Alzheimer's disease and mild
cognitive impairment (MCI), central nervous system damage resulting from
stroke, ischemias including cerebral ischemia (both focal ischemia,
thrombotic stroke and global ischemia (for example, secondary to cardiac
arrest), and trauma. Neurodegenerative disorders in which PDE4 inhibition
may be useful include nerve degeneration or nerve necrosis in disorders
such as hypoxia, hypoglycemia, epilepsy, and in cases of central nervous
system (CNS) trauma (such as spinal cord and head injury), hyperbaric
oxygen convulsions and toxicity, dementia e.g. pre-senile dementia, and
AIDS-related dementia, cachexia, Sydenham's chorea, Huntington's disease,
Parkinson's Disease, amyotrophic lateral sclerosis (ALS), Korsakoff's
syndrome, and imbecility relating to a cerebral vessel disorder. Further
disorders in which PDE4 inhibition might prove useful include
neuropathies of the central and peripheral nervous system (including, for
example, IgA neuropathy, membranous neuropathy and idiopathic
neuropathy), chronic inflammatory demyelinating polyneuropathy,
transverse myelitis, Gullain-Barre disease, encephalitis, and cancers of
the nervous system. Disorders of CNS function in which PDE4 inhibitors
may find use include sleeping disorders, schizophrenia, depression,
depression or other symptoms associated with Premenstrual Syndrome (PMS),
and anxiety.

[0223]Furthermore, the compounds of the present invention may also be
useful in inhibiting PDE4 activity for the amelioration of systemic
disorders including systemic hypotension associated with septic and/or
toxic hemorrhagic shock induced by a wide variety of agents; as a therapy
with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short
term immunosuppression in transplant therapy.

[0224]Still other disorders or conditions which may be treated by the
compounds of the subject invention include the prevention or treatment of
cancer, such as colorectal cancer, and cancer of the breast, lung,
prostate, bladder, cervix and skin. Compounds of the invention may be
used in the treatment and prevention of neoplasias including but not
limited to brain cancer, bone cancer, leukemia, lymphoma, epithelial
cell-derived neoplasia (epithelial carcinoma) such as basal cell
carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer,
mouth cancer, esophageal cancer, small bowel cancer and stomach cancer,
colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian
cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such
as squamous cell and basal cell cancers, prostate cancer, renal cell
carcinoma, and other known cancers that effect epithelial cells
throughout the body. The present compounds and methods may also be used
to treat the fibrosis which occurs with radiation therapy. The present
compounds and methods may be used to treat subjects having adenomatous
polyps, including those with familial adenomatous polyposis (FAP).
Additionally, the present compounds and methods may be used to prevent
polyps from forming in patients at risk of FAP.

[0225]The compounds of the subject invention may be used in the treatment
of ophthalmic diseases, such as dry eye, glaucoma, corneal
neovascularization, optic neuritis, Sjogren's syndrome, retinal ganglion
degeneration, ocular ischemia, retinitis, retinopathies, uveitis, ocular
photophobia, and of inflammation and pain associated with acute injury to
the eye tissue. Specifically, the compounds may be used to treat
glaucomatous retinopathy and/or diabetic retinopathy. The compounds may
also be used to treat post-operative inflammation or pain as from
ophthalmic surgery such as cataract surgery and refractive surgery.

[0226]Moreover, compounds of the subject invention may be used in the
treatment of menstrual cramps, dysmenorrhea, premature labor,
endometriosis, tendonitis, bursitis, skin-related conditions such as
psoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis,
lichen planus, scleritis, scleroderma, dermatomyositis, and the like.
Other conditions in which the compounds of the subject invention may be
used include diabetes (type I or type II), atherosclerosis, congestive
heart failure, myocarditis, atherosclerosis, cerebral ischemia,
angiogenesis, pulmonary hypertension, and aortic aneurysm.

[0227]The present compounds may also be used in co-therapies, partially or
completely, in place of other conventional anti-inflammatory therapies,
such as together with steroids, NSAIDs, COX-2 selective inhibitors,
5-lipoxygenase inhibitors, LTB4 antagonists and LTA4 hydrolase
inhibitors. The compounds of the subject invention may also be used to
prevent tissue damage when therapeutically combined with antibacterial or
antiviral agents.

[0228]Besides being useful for human treatment, the compounds and
formulations of the present invention are also useful for veterinary
treatment of companion animals, exotic animals and farm animals,
including mammals, rodents, and the like. More preferred animals include
horses, dogs, and cats.

General Synthetic Methods for Preparing Compounds

[0229]The following schemes can be used to practice the present invention.

[0235]A mixture of methyl 2-amino-3-(cyclopentyloxy)-4-methoxybenzoate
(655 mg, 2.47 mmol) and formamide (6 mL) was heated at 190° C.
under N2. After 5.5 h, the reaction was allowed to cool to rt
overnight, and a precipitate formed. Water (20 mL) was added, and the
mixture was stirred vigorously for 2 min. The precipitate was filtered,
washed with water (20 mL), and dried under vacuum to give
8-(cyclopentyloxy)-7-methoxyquinazolin-4(3H)-one: MS (ESI): 261.5.

Step 5

[0236]N,N-Dimethylformamide (1 drop) was added to a mixture of
8-(cyclopentyloxy)-7-methoxyquinazolin-4(3H)-one (223 mg, 0.86 mmol),
phosphoryl trichloride (0.16 mL, 1.7 mmol), and 1,2-dichloroethane (4 mL)
at rt under N2. The reaction was refluxed for 14 h, allowed to cool
to rt, and then diluted with dichloromethane (75 mL). This solution was
washed with sat'd NaHCO3 (75 mL×2), and then each aqueous wash
was extracted with dichloromethane (75 mL). The combined extracts were
dried, filtered, and concentrated to give
4-chloro-8-(cyclopentyloxy)-7-methoxyquinazoline (unstable; must be used
immediately).

[0248]N,N-Dimethylformamide (0.015 mL, 0.2 mmol) was added to a mixture of
8-(cyclopentyloxy)-7-methoxyquinolin-4(1H)-one (518 mg, 2.0 mmol),
phosphoryl trichloride (0.40 mL, 4.3 mmol), and 1,2-dichloroethane (6 mL)
at rt under N2. The reaction was refluxed for 14.5 h, allowed to
cool to rt, and then diluted with dichloromethane (40 mL). This solution
was washed with sat'd NaHCO3 (50 mL×2), and then each aqueous
wash was extracted with dichloromethane (40 mL). The combined extracts
were dried, filtered, and concentrated to give
4-chloro-8-(cyclopentyloxy)-7-methoxyquinoline. MS (ESI): 277.9.

[0258]A solution of (E)-3-[2-(cyclopentyloxy)-3-methoxyphenyl]acryloyl
azide (5.38 g, 18.7 mmol) and diphenylmethane (30 mL) was added over 1 h
to diphenylmethane (70 mL) maintained at 200° C. (internal
temperature) under N2. After the addition was complete, the reaction
temperature was raised to 225° C. over 5 h, maintained for an
additional 40 min, and then allowed to cool to rt. The reaction mixture
was diluted with petroleum ether (100 mL) and poured onto a silica gel
column. The column was flushed with hexanes to remove the
diphenylmethane, and standard chromatography (3:2→1:4;
hexanes:ethyl acetate) gave
5-(cyclopentyloxy)-6-methoxyisoquinolin-1(2H)-one: MS (ESI): 260.0.

[0266]A mixture of copper (II) bromide (18.5 g, 82.7 mmol) and ethyl
acetate (40 mL) was heated at 85° C. A suspension of
1-(2,3-dihydroxy-4-methoxyphenyl)ethanone (9.20 g, 46 mmol) and
chloroform (80 mL) was added, and the mixture was refluxed for 16 h. The
reaction was allowed to cool to rt, filtered, and concentrated to give
2-bromo-1-(2,3-dihydroxy-4-methoxyphenyl)ethanone: MS (ESI): 260.8.

Step 2

[0267]Potassium carbonate (12.7 g, 92 mmol) was added to a solution of the
crude 2-bromo-1-(2,3-dihydroxy-4-methoxyphenyl)ethanone and acetonitrile
(250 mL) at rt. After 2 h, more potassium carbonate (19 g, 138 mmol) was
added followed by bromocyclopropane (9.9 mL, 92 mmol). The mixture was
heated at reflux for 16 h and then allowed to cool to rt. The reaction
was concentrated, diluted the ethyl ether, and washed with 1N HCl. The
organic extract was dried, filtered, concentrated, and purified by silica
gel chromatography (0→30% EtOAc/hexanes) to afford
7-(cyclopentyloxy)-6-methoxybenzofuran-3(2H)-one: MS (ESI): 249.0.

[0300]A mixture of
8-(cyclopentyloxy)-4-hydroxy-7-methoxyquinolin-2(1H)-one (350 mg, 1.3
mmol), ammonium acetate (4.0 g, 52 mmol), and anhydrous m-xylene (10 mL)
was heated at 150° C. under N2 for 48 h and then allowed to
cool to rt. The mixture was concentrated to dryness, diluted with water
(25 mL), stirred for 2 min, sonicated for 1 min, and then stirred for 5
min. The free-flowing solid was filtered, washed with water (25 mL), and
pumped to dryness to give
4-amino-8-(cyclopentyloxy)-7-methoxyquinolin-2(1H)-one: MS (ESI): 274.9.

[0327]The activity of the compounds in Examples 1-30 as PDE4 inhibitors is
illustrated in the following assay. The other compounds listed above,
which have not yet been made and/or tested, are predicted to have
activity in this assay as well.

Novel PDE/AK Biological Activity Assay Protocol

[0328]Phosphodiesterases regulate the activity of the second messenger
cyclic adenosine monophosphate (cAMP) by hydrolyzing cAMP to adenosine
monophosphate (AMP). We developed a novel coupled PDE/AK bioluminescent
high-throughput assay to measure the activity of phosphodiesterases. In
the PDE/AK assay, the AMP produced from the hydrolysis of cAMP by
phosphodiesterase is converted to adenosine diphosphate (ADP) by the
phosphotransferase activity of adenylate kinase (also known as ADK or
myokinase). Adenylate kinase will catalyze the conversion of 1 mole of
AMP and 1 mole of ATP into 2 moles of ADP. Thus the conversion of AMP to
ADP will result in the subsequent loss of ATP. The decrease in ATP
concentration can be monitored as light output using luciferase in a
reaction that requires ATP to produce light. The PDE/AK assay uses
luciferase, which catalyzes the production of light from ATP present in
the reaction mix. The amount of emitted light is inversely proportional
to the level of AMP present in the reaction. Test compounds are incubated
with the phosphodiesterases and phosphodiesterase inhibitors will
decrease the rate of cAMP hydrolysis and decrease the subsequent
production of AMP. Thus phosphodiesterase inhibitors will decrease the
conversion of ATP to ADP and result in the greatest emission of light.

[0329]Compounds may be screened for functional potency in in vitro
biochemical assays for their ability to inhibit the activity of
phosphodiesterase (PDE) enzymes. A novel coupled PDE/AK assay was
utilized to measure the inhibitory activity of compounds on PDE isoforms.
The catalytic domain of PDE4B was fused to an amino-terminus
hex-histidine affinity tag and purified. PDE4B enzyme was incubated with
compounds for 10 minutes. Cyclic AMP substrate, ATP and adenylate kinase
were then added to the PDE enzyme mix and incubated for 45 minutes at
room temperature. A commercial ATP detection assay, Perkin Elmer's
easyLite ATP detection reagent, was then added to measure the relative
amount of ATP present in the reaction. After 10 minute incubation, the
luminescent signal was quantitated with either the Perkin Elmer Viewlux
or Molecular Devices Acquest or Analyst. Roflumilast and Rolipram are the
positive controls used in the assay.

[0330]The PDE/AK assay can be performed with any cAMP dependent
phosphodiesterase, and can be performed in 96-, 384-, or 1536-well
plates. Unlike other phosphodiesterase activity assays, the PDE/AK assay
does not require radioactive substrates, modified substrates, beads, or
antibodies, which each have disadvantages. Specifically, the use of
radioactive substrates in a phosphodiesterase activity assay requires
special protocols for handling and waste disposal, and reduced
throughput. Modified substrates add the additional complexity of
potentially altering the binding to the phosphodiesterase catalytic site.
Fluorescently modified substrates may cause fluorescence artifacts that
may interfere in the interpretation of assay results. The use of beads
that selectively bind to either the cAMP or AMP may cause an additional
complexity in reagent handling. The use of antibodies that selectively
bind to either cAMP or AMP can be extremely costly with a relatively
small signal to noise ratio. Therefore, the novel PDE/AK assay represents
a simple, cost-effective alternative to known methods.

[0331]Additionally, the PDE/AK assay's mechanism offers advantages which
make it useful for comparison to other phosphodiesterase activity assays.
In conventional assays in which cAMP concentration is inversely
proportional to the output of bioluminescence (such as Cambrex
Biosciences's PDELight), phosphodiesterase catalyzes the hydrolysis of
cAMP to AMP that is subsequently converted to ATP, consumed by a
luciferase enzyme, and results in an increased bioluminescent output. A
phosphodiesterase inhibitor prevents the hydrolysis of cAMP to AMP and
consequently results in a decreased bioluminescent output. However,
compounds which exhibit luciferase inhibition activity would score as a
false positive for PDE inhibition in the conventional assay. In contrast,
the novel PDK/AK assay would not score luciferase inhibitors as false
positive for PDE inhibition because inhibition of PDE activity would
result in increased bioluminescence. However, compounds that are capable
of inhibiting both PDE and luciferase would be false negatives. Compounds
that inhibit adenylate kinase would score as false positives in the novel
PDE/AK assay. Use of both types of assay, and comparison of the data from
both, would yield a richer and more reliable data set.

[0332]Accordingly, contemplated herein is a method for the detection and
quantitation of PDE inhibition which uses adenylate kinase coupled to an
ATP-depleting assay.

[0333]In certain embodiments, said method comprises the steps of:
[0334]1. A first incubation, of PDE, or an isolated isoform thereof, with
a compound to be tested; [0335]2. Addition of ATP, cAMP, and AK
substrates; [0336]3. A second incubation of said PDE; [0337]4. Coupling
to a means for readout of ATP-depletion; and [0338]5. Readout.

[0339]In further embodiments, said first incubation is for between about 5
and about 15 minutes; in yet further embodiments, said first incubation
is for about 10 minutes.

[0340]In further embodiments, said second incubation is for longer than
about 30 minutes; in yet further embodiments, said sufficient length of
time is between about 30 minutes and about one hour; in even further
embodiments, sufficient length of time is about 45 minutes.

[0341]In further embodiments, said readout means is a luciferase assay. In
yet further embodiments, said luciferase assay is a Perkin Elmer easyLite
assay.

[0342]In further embodiments, said readout is done on a machine for
detecting a luminescent signal. In yet further embodiments, said machine
is selected from the group consisting of a Perkin Elmer Viewlux, a
Molecular Devices Acquest, and a Molecular Devices Analyst.

[0344]A more detailed description of the assay used herein may be found in
Naglehout, T J et al. 2005, "Preservation of Tear Film Integrity and
Inhibition of Corneal Injury by Dexamethasone in a Rabbit Model of
Lacrimal Gland Inflammation-Induced Dry Eye,"J. Ocular Pharm. Ther.,
21:2. 139-148, the disclosure of which is hereby incorporated by
reference as if written herein in its entirety.

Initiation of Dry Eye and Treatment

[0345]Rabbits (n=4/group) were randomized into treatment groups and dosed
topically BID with maxidex vehicle or test drug beginning one day prior
to initiation of dry eye. Each rabbit received bilateral lacrimal gland
injections of saline or ConA (300 μg/30 μl) and topical ocular
dosing was continued BID throughout the study.

Corneal Staining

[0346]Desiccation was initiated 1-2 hours following lacrimal gland
injection by placing conscious rabbits in the environmental chamber
(10-15% humidity/72° F.). Following 72 consecutive hours of
exposure to this dry environment, the animals were anesthetized and
sutures were placed in each upper and lower eyelid and lifted to form a
corneal/conjunctival cup. Methylene blue dye (1 mL, 1% in dH2O) was
added to the cup for three minutes and the excess removed by washing with
200 mL BSS®. The contralateral eye was then stained using the same
procedure. Rabbits were euthanized immediately following the staining
procedure and the eyes were excised. The corneas were isolated with a
trephine and the 9.5-mm punch of the cornea was placed in 2 mL
acetone/saturated sodium sulfate (7:3, vol./vol.). Absorbance of the
extracted dye was determined at 660 nm.

Tear Breakup Time (TBUT)

[0347]TBUT was quantified in a separate group of treated animals. TBUT was
determined by instilling 5 μL sodium fluorescein into the cul de sac
and manually blinking the lids to distribute the fluorescein within the
tear film. Under slit lamp observation, the eye was held open and the
time whereby one or more black spots or streaks appeared in the
precorneal tear film was recorded. The rabbits were euthanized 3 days
following ConA inj ection.

[0348]Data reported as NT refers to the example having been not tested.

[0349]From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and without
departing from the spirit and scope thereof, can make various changes and
modifications of the invention to adapt it to various usages and
conditions.